SUMMARY Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease (AD), affecting more than 1 million people in the United States. Because age is the major risk factor, the prevalence of both diseases is steadily increasing as our population ages. PD belongs to the group of protein misfolding neurodegenerative diseases that are due to the misfolding and aggregation of a host protein. While many of the steps leading to neurodegeneration in PD are still unknown, ?-synuclein (?-syn) appears to be central to the pathological process. Lewy Bodies, the neuropathological hallmark of PD, are constituted mainly of phosphorylated, aggregated ?-syn. There is currently no disease-modifying treatment for PD or other ?-synucleinopathies and there is an urgent need for new treatment options. The goal of the present phase I STTR application is to develop and validate a high-throughput screening (HTS)-ready assay for the large-scale unbiased identification of compounds reducing the levels of a recently identified, highly neurotoxic, form of ?-syn, called p?-syn*. Completion of the proposed work plan will enable an HTS campaign and open up the way to develop new neuroprotective compounds, thereby addressing a critical barrier to progress in the field of therapeutic intervention for PD and other synucleinopathies. ! 1!